Liquid chromatography (LC)—tandem quadrupole mass spectrometry (MS/MS), or (LC-MS/MS), has been widely applied for protein, peptide, and metabolite quantitation in proteomics and metabolomics studies. Sensitivity is important for reliable detection and quantitation of low-abundance species in complex biological matrices. Recent developments including incorporation of an electrodynamic ion funnel (IF), an S-lens, or an RF only quadrupole ion guide as a front-end interface to a triple quadrupole MS instrument have improved ion sampling and ion transport from an ESI ion source to an MS detector resulting in an increase in LC-MS/MS sensitivity. However, the limit of detection (LOD) for current state-of-the-art instruments remains inadequate for reliable quantitation of low (e.g., ng/mL) quantities of biologically-significant proteins present in complex biological matrices in part due to elevated levels of chemical background typically observed in high throughput modes of operation at shorter LC gradients. Accordingly, new instrument developments are needed that provide the required sensitivity for reliable quantitation of biologically-significant proteins present at low quantities in complex biological matrices. The present invention meets these needs.